NCT01092130CompletedPhase 2
An Open-label, Blinded-endpoint, Randomized, Prospective Trial Investigating the Effects of Vitamin D Administration on Plasma Renin Activity in Patients With Stable Chronic Heart Failure
University Medical Center Groningen1 site in 1 country101 target enrollmentStarted: March 2010Last updated:
Conditions
Interventions
Drugs
Trial Snapshot
- Phase
- Phase 2
- Status
- Completed
- Enrollment
- 101
- Locations
- 1
- Primary Endpoint
- Plasma Renin Activity
Study Overview
Brief Summary
The renin-angiotensin system (RAS) is a regulatory system that plays an essential role in patients with chronic heart failure (CHF). Plasma renin activity (PRA) is a strong and independent predictor of outcome, also in the presence of ACE inhibitors (ACE-i) and/or angiotensin receptor blockers (ARBs). Recently, it has been shown that vitamin D regulates renin transcription by activating the vitamin D receptor (VDR). Thus, specific activation of the VDR represents a novel target for therapeutic intervention in CHF. Currently, clinical data are lacking. The investigators aim to investigate the effect of the administration of vitamin D in patients with CHF.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Out clinical patients ≥ 18 years of age, male or female.
- •Patients with a diagnosis of chronic heart failure (NYHA Class II, III or IV).
- •Patients must at least be treated with an ACE-i at a stable dose (at least enalapril 10 mg daily or any other ACE-i, e.g. ramipril, quinapril, lisinopril, fosinopril, perindopril, trandolapril; on equivalent doses, or maximum tolerated dose) or if intolerant to ACE-i with ARB therapy (Candesartan 8 mg daily or any other ARB in equivalent dose, or maximum tolerated dose) for at least 4 weeks prior to visit
- •Patients must be treated with a beta blocker unless contraindicated or not tolerated at a stable dose for at least 4 weeks prior to visit 1 (for patients not on target dose or in absence of that medication, the reason should be documented).
- •Concomitant use of ACE-i and/or ARB and/or aldosterone antagonist is permitted.
Exclusion Criteria
- •LVEF >45% at visit 1 (local measurement, measured within the past 12 months assessed by echocardiogram, MUGA or ventricular angiography).
- •History of hypersensitivity to the study drugs.
- •Patients with phenylketonuria.
- •Patients with fructose intolerance.
- •Current acute decompensated heart failure.
- •Hypercalcemia (>2.65 mmol/l, corrected for albumin).
- •Hypercalciuria.
- •Estimated glomerular filtration fraction (eGFR) between 30 and 60 ml/min/1.73m2 as measured by the modified of diet in renal disease (MDRD) formula.
- •Nephrolithiasis.
- •Sarcoidosis.
- •Use of the following medication: corticosteroids, thyroxin, anti epileptic drugs, tetracyclines, quinolones
- •Intake of supplements containing vitamin D and/or calcium.
- •Acute coronary syndrome, stroke, transient ischemic attack, cardiac, carotid or major vascular surgery, percutaneous coronary intervention (PCI) or carotid angioplasty, within the past 3 months.
- •Coronary or carotid artery disease likely to require surgical or PCI.
- •Right heart failure due to severe pulmonary disease.
- •Diagnosis of peripartum or chemotherapy induced cardiomyopathy within the last year.
- •Patients with a history of heart transplant or who are on a transplant list or with LVAD device (left ventricular assistance device).
- •Documented ventricular arrhythmia with syncopal episodes within past 3 months that is untreated.
- •Documented history of ventricular tachycardia or ventricular fibrillation without ICD (internal cardiac defibrillator).
- •Symptomatic bradycardia, or second or third degree heart block without a pacemaker.
- •Implantation of a CRT (cardiac resynchronization therapy) device within prior 3 months.
- •Presence of hemodynamically significant mitral and /or aortic valve disease, except mitral regurgitation secondary to left ventricular dilatation.
- •Presence of hemodynamically significant obstructive lesions of left ventricular outflow tract, including aortic stenosis.
- •Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of study drugs.
- •Any history of pancreatic injury, pancreatitis or evidence of impaired pancreatic function/injury as indicated by abnormal lipase or amylase.
- •Primary liver disease considered to be life threatening.
- •Currently active gastritis, duodenal or gastric ulcers, or gastrointestinal/rectal bleeding during the 3 months prior to Visit
- •History or presence of any other diseases (i.e. including malignancies) with a life expectancy of < 5 years.
- •Current double-blind treatment in heart failure (HF) trials.
- •Participation in an investigational drug study at the time of enrollment or within the past 30 days or 5 half lives of enrollment whichever is longer.
- •Any surgical or medical condition that in the opinion of the investigator or medical monitor would jeopardize the evaluation of efficacy or safety.
- •History of noncompliance to medical regimens and patients who are considered potentially unreliable.
- •Pregnant or lactating women.
- •Treatment with any of the following drugs within the past 4 weeks prior to Visit 1 (T0):
- •Direct renin inhibition including Aliskiren
- •Intravenous vasodilator and/or inotropic drugs
Arms & Interventions
Vitamin D
Experimental
Patients were randomized by an automated computer system to 2000 IU oral cholecalciferol once daily or control (i.e. no extra medication), in a 1:1 ratio for a period of six weeks. Blood was collected in a sitting position on visits 2-4 and patients were asked to collect 24h urine samples prior to visits 2 and 4. Heart failure medication was maintained unchanged throughout the trial. Changes in diuretic dose were permitted if necessary to treat decompensation or renal dysfunction.
Intervention: Vitamin D (Drug)
Outcomes
Primary Outcomes
Plasma Renin Activity
Time Frame: 6 weeks
The primary endpoint of this study is the PRA after 6 weeks of treatment with vitamin D compared to the PRA after 6 weeks without treatment.
Secondary Outcomes
- To evaluate the effect of vitamin D administration on different markers of the vitamin D cascade, such as vitamin D, calcium, phosphate and PTH (parathyroid hormone)(6 weeks)
- To evaluate the effect of vitamin D administration on plasma levels of NT-proBNP(6 weeks)
- Safety endpoints are biochemical indices of kidney function and bone homeostasis(6 weeks)
- To evaluate the effect of vitamin D administration on plasma values of additional markers of renin-angiotensin system activity, including angiotensin II, angiotensin converting enzyme activity and chymase activity(6 weeks)
- To evaluate the effect of vitamin D administration on NYHA-class(6 weeks)
- To evaluate the effect of vitamin D administration on extracellular matrix markers (PIIINP, PICP, PINP) and degradation markers (MMP1, MMP9, TIMP1, MMP1/TIMP1-complex)(6 weeks)
- To evaluate the effect of vitamin D administration on urinary levels of markers of glomerular and tubular damage(6 weeks)
Investigators
Willem-Peter Theodoor Ruifrok
MD, PhD
University Medical Center Groningen
Study Sites (1)
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